Jerome H. Check1, 2 and Jasmine Aly1
(1)
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cooper Medical School of Rowan University, Camden, NJ, USA
(2)
Cooper Institute for Reproductive Hormone Disorders, P.C., Mt. Laurel, NJ, USA
Jerome H. Check (Corresponding author)
Email: laurie@ccivf.com
Jasmine Aly
Email: Aly-Jasmine@Cooperhealth.edu
Abstract
The presence of antisperm antibodies (ASA) coating sperm can be a cause of infertility. However, their presence is not an invariable cause of infertility. This lack of consistency may be related to the percentage of sperm that are coated with the ASA or the concentration of ASA on each sperm. Also sometimes the explanation for achieving a pregnancy despite the presence of ASA may be related to the ASA directed against inert antigens. Based on studies showing very poor pregnancy rates following intrauterine insemination (IUI) of sperm where 100 % are coated with ASA, one can make a reasonable assumption that the majority of males with a high percentage of their sperm coated with ASA will be a factor causing a couple’s infertility. Another reasonable assumption is that the majority of ASA must effect the fertilization process as the negative effects of immobilizing ASA would be circumvented by IUI. One of the best treatment options for overcoming ASA is to perform in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). Though conventional insemination of oocytes may be more effective than IUI, the ASA can sometimes lead to failure of sperm to bind to the zona pellucida leading to low fertilization rates. Unfortunately, IVF with ICSI is very expensive. A less expensive option is to try to neutralize the adverse effects of the ASA before IUI. There is evidence that this can be accomplished by treatment of the sperm prior to IUI with a protein digestive enzyme, e.g., chymotrypsin.
15.1 Introduction
A very recent manuscript was published by a group well known to the andrology field entitled “Functional defect of sperm and fertility impairment in men with antisperm antibodies” by Bozbedomov et al. [4]. In their introduction, they mention that “antisperm antibodies (ASA) have been detected in 8–21 % of infertile men; however the presence of ASA has also been detected in 12–19 % of fertile men” [4]. They quote references from Krause et al., Francavilla and Barbonetti, Vasquez-Leven et al. [4, 24, 30, 46].
The study by Bozbedomov et al. discusses the results of the largest study to date, which evaluated 1794 infertile couples by Leushuis et al. [4, 33]. The conclusion from this study states “that the MAR test is not able to predict spontaneous pregnancy chances.” Their conclusion from Leushuis et al. about measuring ASA was that “It’s routine use in the basic fertility workup for identification of couples with low spontaneous pregnancy chances is not justified when a threshold of >50 % is used” [33].
The results of these studies suggested no higher frequency of significant ASA levels (>50 %) in fertile vs. subfertile males and no evidence of a significant impairment of fertility even when ASA are present. This has led to the majority of present day infertility specialists abolishing the measuring of ASA in their routine practice.
The objective of this manuscript is to explore whether it is useful to measure ASA routinely or in certain specific circumstances. In addition, this manuscript will also examine if their presence should influence treatment by assisted reproductive technology, i.e., intrauterine insemination (IUI) or in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). If routine measurement of ASA is not recommended, an objective of this article is to carefully review the literature to determine if there are any specific circumstances that would warrant ASA testing. Another objective is to consider whether the seemingly lack of correlation between ASA and fertility outcome or lack of increased frequency of ASA in infertile couples may actually be related to the parameters set for a positive ASA level. This study will address if the cutoff of >50 % is too low, i.e., will levels >80 % or levels restricted to 100 % show better correlation. Finally, the intent of this manuscript is to explore the relative value of treatment options in infertile cases that seem to be related in part, or in whole, to ASA, i.e., is IVF with ICSI the best option? How do other treatment options, e.g., intrauterine insemination (IUI) compare? Are there other methods to improve the success of IUI when ASA are present?
15.1.1 Mechanism by Which ASA May Impair Fecundity
1. 1.
2. 2.
15.1.2 Treating Sperm Bound with ASA with Chymotrypsin Galactose Prior to IUI
A study was performed involving 16 couples where all infertility factors were corrected except a poor properly timed postcoital test (no sperm with progressive linear motion) despite what appeared to be appropriate quality cervical mucus [3]. Furthermore, the male partner was found by immunobead testing to have >50 % of sperm with ASA. Intrauterine insemination was performed with all the males ejaculating into 5 ml of equal parts of modified human tubal fluid buffered with HEPES solution and 7.5 % bovine serum albumin in an attempt to dilute the sperm to theoretically negate the attachment of antibodies at the time of ejaculation. Another group ejaculated into media with the protein digestive enzyme chymotrypsin with galactose in order to cleave part of the ASA immunoglobulin molecule to neutralize its function prior to sperm washing. The 16 couples were randomly assigned one of the two sperm preparations, and if no pregnancy was achieved, the other preparation was used for the second cycle of treatment [3]. With each failure, they were switched to the other protocol for the next treatment [3]. There were 65 treatment cycles – 32 with chymotrypsin/galactose and 33 with albumin. Pregnancies were achieved in 8 of 32 (25 %) cycles following IUI with chymotrypsin/galactose vs. only one of 33 (3 %) performed with sperm ejaculated into albumin fortified media [3]. When 100 % of sperm was found to be coated by ASA, Francavilla et al. found no live pregnancies following 119 IUI cycles [25]. In contrast, a pregnancy rate of 25 % per cycle was found following IUI with chymotrypsin-treated sperm when evaluating the subset of couples whose male partner had 100 % of the sperm coated with ASA [3].
Interestingly the pregnancy rate for female partners of males with 100 % ASA was 75 % with three treatment cycles when treated with chymotrypsin/galactose. This suggests that the antibodies that may inhibit the fertilization process rather than the antibodies that impede sperm from reaching the oocyte play a significant role in infertility and they need to be neutralized prior to insemination. Though IUI is less expensive than IVF, nevertheless, it still adds expense and missed time at work. Though significant levels may only be present in <5 % of the couples, theoretically, it makes sense to measure this potential infertility factor prior to initiating any therapy. There do not appear to be any subsequent studies refuting or corroborating the beneficial effects of treating sperm with chymotrypsin/galactose prior to IUI.
15.1.3 The Use of In Vitro Fertilization (IVF) with Intracytoplasmic Sperm Injection (ICSI) for Treating ASA Related Infertility
The patient’s choice of IUI or IVF with ICSI is frequently determined by economics and rules of the insurance companies. Most insurances that cover IVF-ET and ICSI will approve this procedure if a high percentage of the sperm are laden with ASA. Nevertheless those without sufficient funds or insurance coverage may elect to try IUI first. Based on the poor pregnancy rates demonstrated by Francavilla et al., and the good success rates demonstrated by Bollendorf et al. with sperm first pretreated with chymotrypsin/galactose, if IUI is planned, it makes more sense to first treat with the aforementioned protein digestive enzyme [3, 25].
However, experience dictates that most treating physicians are not aware that enzymatic pretreatment before IUI is an option. Even if they read about the procedure, they may be reluctant to use it because of lack of experience. Thus, if ASA is detected on the sperm, and if the decision is made to try IUI first, many infertility specialists will perform the procedure without any pretreatment of the sperm hoping that either the antibodies are directed to inert antigens or merely to immobilizing antibodies, and therefore, in theory, by bypassing the cervical mucus, IUI would overcome the problem.
Infertility specialists who are confronted with couples who have failed to conceive in other infertility practices, and where the female partner has failed to conceive with IUI either with or without the knowledge of the existence of ASA being present, the option of chymotrypsin pretreatment of sperm prior to IUI or IVF-ET with or without ICSI should be considered.
Based on the very poor results of IUI without enzymatic pretreatment for couples whose male partners have 100 % of the sperm coated with ASA, one must assume that the ASA must be directed in a high frequency to antigens involved in the fertilization process not only involved in immobilization. Thus, conventional IVF, where sperm is merely added to the oocyte, could result in low fertilization rates with subsequent poor pregnancy rates if a high percentage of the time the ASA is directed toward antigens involved in the fertilization process. The use of ICSI would negate sperm-zona pellucida binding problems and would overcome the first part of oocyte activation if that was a problem by acting as a pseudo-trigger [17].
15.1.4 IVF with Conventional Insemination with Sperm Pretreated with Chymotrypsin
As described in the previous section, before ICSI, chymotrypsin was found to improve pregnancy rates following IUI. Theoretically, if there was a high percentage of sperm coated by ASA, but not 100 %, there may be enough sperm without ASA to fertilize the oocyte in view of the large number of sperm used for conventional insemination. A study was performed comparing fertilization rates and subsequent pregnancy rates following conventional insemination with sperm with 100 % ASA coating, which were either pretreated with chymotrypsin or just ejaculated into culture medium (to allow dilution of ASA in case, a significant amount is added to the sperm at the time of ejaculation) [29]. The study did show a low fertilization rate of 27 % using conventional oocyte insemination without enzymatic treatment (21 cycles in 11 patients). The fertilization rate was significantly higher in those using enzymatic pretreatment (47 % – 38 cycles in 25 patients). The clinical pregnancy rates were twice as high with chymotrypsin pretreatment 21 % vs. 9.5 % (not statistically significant) [29]. The study was published in the early days of IVF-ET (1995) and thus at a time when pregnancy rates with IVF-ET were much lower than today.
In the aforementioned study, failed fertilization occurred in 13 of 59 (22 %) of cycles and 11 of these occurred in cycles not using enzymatic pretreatment [29]. Interestingly a requirement for the study was failure to conceive after a minimum of 6 IUI cycles (without chymotrypsin therapy) thus hopefully excluding cases of ASA directed against inert antigens or antigens only effecting immobilization [29].
15.1.5 The Use of ICSI for Sperm Coated with ASA
Unfortunately there are no studies comparing enzymatic pretreatment of sperm using conventional oocyte insemination vs. ICSI. However, there is a study comparing the efficacy of chymotrypsin-treated sperm followed by IUI vs. IVF with ICSI [14]. Again males with 100 % of the sperm coated for ASA were selected for comparison. There were 17 women inseminated with chymotrypsin-pretreated sperm in 47 IUI cycles vs. 25 women having IVF with ICSI in 38 IVF-ET cycles. There was a significantly higher pregnancy rates per cycle with IVF with ICSI (28.9 %) vs. IUI with enzymatically treated sperm 10.6 % [14]. The pregnancy rate per patient was 29.4 % with IUI (avg. 7.7 cycles) vs. 44 % for IVF with ICSI (44 %). Considering the marked difference in price, chymotrypsin pretreatment with IUI seems to be a legitimate alternative treatment [14]. Though this study was performed later than the aforementioned study of chymotrypsin pretreatment before conventional therapy, the study was published in 2004 at a time when there was not as much experience with ICSI [14].
The first studies showing the efficacy of IVF with ICSI were published in 1995 by Lahteenmaki et al. and by Nagy et al. [32, 37]. These studies were confirmed by two subsequent studies in 1997 and 2000 [18, 20].
There has been some question as to whether ASA on sperm could lead to some postfertilization issues that could result in clinical pregnancies but result in higher miscarriage rates. Lahteenmaki et al. found a miscarriage rate in 38 % (5/13) in those with ASA vs. zero % for controls [32]. Check et al. found a 14 % miscarriage rate in those with ASA <50 % vs. 25 % for those with >80 % [18]. In contrast, Clarke et al. found no increase in miscarriage rates [20]. This issue has not been resolved to date.
15.1.6 The Future and Historical Perspective
The ultimate study to determine the influence of the presence of ASA on sperm and the efficacy of various treatment options would enlist a multicenter randomized controlled trial with various treatment options in couples with all female factors corrected. The couples would be randomized to one of four groups: 3 cycles of intercourse only, 3 cycles of IUI with sperm not treated with protein digestive enzymes, conventional oocyte insemination, and the last treatment group, IVF with ICSI. Ideally, inert antigens could be determined and those with exclusive ASA to inert antigens would be excluded. The data would then be stratified according to the percentage of sperm coated with ASA.
It is highly unlikely that such a study could ever be performed because of the relatively low percentage of males with ASA, especially with a high percentage of sperm coated with ASA. Furthermore as mentioned, there is much less interest from infertility specialists even measuring ASA.
Besides the low prevalence, other factors contribute to disinterest. In the United States, one of the problems is that CLIA (Clinical Laboratory Improvement Amendments) requires certain criteria for ASA testing. CLIA requires positive and negative controls performed each day of testing. Immunobeads IgG were sold by Bio-Rad; however, the company did not sell controls. Fertility Solutions, Inc. introduced positive and negative controls for indirect testing.
However, Bio-Rad has discontinued making this product. Therefore, ASA testing is only available today using the sperm MAR assay. Controls are available for indirect testing. However, to perform indirect testing, one needs ASA-negative sperm. One way of obtaining this is to use patient’s own sperm and hope he is negative. Another option is to use a known ASA-negative donor and reimburse him. A final option is to freeze an antibody-negative donor’s sperm in aliquots using a freezing medium without human serum albumin (HAS) since HAS will interfere with the sperm MAR assay. This could be used as a control for direct testing. However, HAS is a common protein used in most commercially available cryopreservation medium.
This dilemma has caused a large majority of infertility centers to discontinue direct antisperm testing. Complicating this is the fact that despite the high costs involved just in controls, there is generally a low insurance reimbursement (sometimes as low as $4.00).
As mentioned earlier, the authors have evaluated ASA using the direct immunobead test in over 6000 males and found positive ASA in 263 using a 50 % cutoff (less with males that are positive with higher cutoff levels). The authors hope to answer some of the questions regarding the influence of ASA in the modern IVF era by evaluating the subset of couples with positive ASA (50 % or higher) undergoing IUI with chymotrypsin pretreatment vs. IVF with ICSI. These couples could be retrospectively matched to the next couple having IVF with ICSI but with sperm negative for ASA.
Such a study unfortunately would not be able to ascertain if in the modern era conventional oocyte inseminated with sperm laden with ASA results in better fertilization rates and lower failed fertilization rates than in the earlier era because the policy of our infertility center is to perform ICSI if ASA is >50 %. However, such a study could still compare fertilization rates with ICSI according to percentage of sperm coated with ASA to sperm without such a coating.
Failed fertilization with conventional insemination is rare when sperm have normal parameters and are negative for ASA (0.1 % in 12,448 IVF cycles evaluated) [11]. A study of the subset of couples where semen parameters are normal and ASA is positive could help determine if ASA can still cause fertilization failure related to defects in phase 2 of oocyte activation. Though only 12 cases of failed fertilization were detected in 12,448 cycles, half were related to sperm not attaching to the zona pellucida (which would be overcome by ICSI) but half would not be corrected [11]. If a fair percentage of low or failed fertilization is found in males with a high percentage of sperm positive for ASA, perhaps some oocytes should be fertilized with the addition of calcium ionophore [17, 41].
The proposed study with greater power than the previous aforementioned ones could possibly help solve the debate as to whether the presence of ASA leads to a higher miscarriage rate even if IVF with ICSI is performed.
One could argue that perhaps ICSI should be performed on everyone rather than using conventional oocyte insemination? First of all, ICSI lowers pregnancy rates following embryo transfer [12, 13, 15]. Furthermore, ICSI adds extra expense to an already expensive procedure and tremendously increases embryologists work load.
The authors suggest that the frequency of ASA in the population be made known to the couple. A discussion with the patient should then follow, offering the option of measuring ASA either before IUI or IVF to prevent the wrong method being used. Perhaps if either the couple or IVF center does not want to test for ASA in all cases, one could consider a properly timed postcoital test to help determine which specific subset of patients may benefit from measurement of ASA [9], as it has been known for over two decades that when sperm are laden with ASA, this can impair sperm progression through the cervical mucus [19, 22, 36].
It is our policy that all couples with positive ASA have IUI with chymotrypsin/galactose pretreatment. Thus, a matched controlled study cannot be performed with our data to determine, in the modern era, whether we can corroborate previous data, suggesting enzymatic pretreatment improves pregnancy rates compared to other methods [3]. Some infertility specialists would argue that IUI is used routinely in most couples, and if ASA was present, the IUI would overcome the problem. However, until proven otherwise, the use of IUI does not seem to overcome the problems of ASA empirically when present in a high percentage of the sperm [25]. As an aside, there is no evidence that IUI improves pregnancy rates in infertile couples where semen parameters are normal and postcoital tests are normal [16]. Perhaps the problems of performing ASA testing, and the apparent severe detriment to the infertile couple if not detected when ASA is present, could reinstitute the inexpensive properly timed postcoital test as a screening test for evaluating the presence or absence of ASA [6, 7, 42].
Finally, the possible presence of ASA in cervical mucus should be mentioned although the frequency is far less common than ASA on sperm [10]. Furthermore, IUI should overcome this problem. Thus, where IUI is performed routinely, or performed for a poor postcoital test, the problem of ASA in the cervical mucus should be corrected assuming ASA is absent in uterine and tubal fluids.
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